DESCRIPTION: HIV-1 leads to a chronic infection that requires long-term administration of suppressive antiretroviral agents, but cannot be cured with currently available interventions. The most dominant barrier against a cure of HIV-1 consists of latently-infected CD4 T cells in which HIV-1 remains transcriptionally silent, and is unaffected by traditional antiretroviral agents. The development of interventional strategies that can reduce the number of latently infected cells and delay viral rebound after treatment discontinuation would be of substantial benefit for many HIV-1 patients. This proposal sets out to explore interventions for curing/eradicating HIV-1 by focusing on effects of IFN-? an immunomodulatory agent that is effective in curing chronic HCV infection. For many years, it has been recognized that IFN-? can effectively reduce HIV-1 viral loads in otherwise untreated patients by approximately one log, indicating that it has potent in vivo activities against actively-replicating HIV- 1, but the role of IFN-? against latently HIV-1 infected cells remains currently unknown. The central hypothesis of this application is that in addition to its effects on actively replicating HIV-1, IFN-? can also exert potent activities aganst the reservoir of latently infected HIV-1 cells, and that these effects are due to a combination of innate, cell-intrinsic and adaptive immune mechanisms. To investigate this, we will focus on a large cohort of HAART-treated HIV-1 infected patients who underwent treatment with IFN-? /Ribavirin (RBV) for treatment of Hepatitis C infection, and from whom large number of PBMC were longitudinally collected for immunologic, virologic and immunogenetic studies. In an initial step, we will use these samples to characterize the reservoir of HIV-1 infected CD4 T cell subsets, and the number of HIV-1 infected cells harboring replication-competent HIV-1 during treatment with IFN-? (specific aim 1, R21 phase). Using samples from the same patients, we will subsequently evaluate immunogenetic characteristics associated with reduction of the HIV-1 CD4 T cell reservoir (specific aim 2, R33 phase) and innate and adaptive effector cell responses (specific aim 3, R33 phase) associated with a reduction of the reservoir of HIV-infected cells during HAART. Subsequently, samples from HIV-1 patients receiving IFN-? and in vitro models of HIV-1 latency will be used to mechanistically analyze how reactivation from viral latency may induce a cellular stress response that increases cellular susceptibility to immune-mediated clearance by innate and adaptive effector cells (specific aim 4, R33 phase), and to investigate cell-intrinsic immune recognition in CD4 T cells that may selectively lead to cell death and apoptosis in cells in which reactivation occurs (specific aim 5, R33 phase). As such, the major deliverable of the proposed project will be an integrated, comprehensive dataset of virologic and immunologic changes occurring during IFN-? treatment of HAART-treated HIV-1 patients, and an improved understanding of immune mechanisms contributing to reduction of the viral reservoir during IFN-? treatment; these data will be very informative for designing future clinicl trials for HIV-1 eradication.